Abstract
Stromal cell-derived factor-1α (SDF-1α) is a ligand for C-X-C chemokine receptor type 4 (CXCR4), which contributes to the metastasis of cancer cells by promoting cell migration. Here, we show that the SDF-1α/CXCR4 axis can significantly increase invasion of esophageal carcinoma (EC) cells. We accomplished this by examining the effects of CXCR4 knockdown as well as treatment with a CXCR4-neutralizing antibody and the CXCR4-specific inhibitor AMD3100. Curcumin suppressed SDF-1α-induced cell invasion and matrix metalloproteinase-2 (MMP-2) promoter activity, cell surface localization of CXCR4 at lipid rafts, and lipid raft-associated ras-related C3 botulinum toxin substrate 1 (Rac1)/phosphatidylinositol 3-kinase (PI3K) p85α/Akt signaling. Curcumin inhibited SDF-1α-induced cell invasion by suppressing the Rac1-PI3K signaling complex at lipid rafts but did not abrogate lipid raft formation. We further demonstrate that the attenuation of lipid raft-associated Rac1 activity by curcumin was critical for the inhibition of SDF-1α-induced PI3K/Akt/NF-κB activation, cell surface localization of CXCR4 at lipid rafts, MMP-2 promoter activity, and cell invasion. Collectively, our results indicate that curcumin inhibits SDF-1α-induced EC cell invasion by suppressing the formation of the lipid raft-associated Rac1-PI3K-Akt signaling complex, the localization of CXCR4 with lipid rafts at the cell surface, and MMP-2 promoter activity, likely through the inhibition of Rac1 activity.
Keywords:
Akt; CXCR4; PI3K; Rac1; SDF-1α; curcumin; esophageal carcinoma; lipid raft; p85α.
© 2012 Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis
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Blotting, Western
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Movement
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Cell Proliferation
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Chemokine CXCL12 / genetics
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Chemokine CXCL12 / metabolism*
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Curcumin / pharmacology*
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Esophageal Neoplasms / drug therapy*
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Esophageal Neoplasms / metabolism
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Esophageal Neoplasms / pathology*
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Flow Cytometry
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Humans
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Immunoprecipitation
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Male
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Membrane Microdomains / drug effects
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Membrane Microdomains / metabolism*
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Middle Aged
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Invasiveness
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism*
Substances
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Antineoplastic Agents
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CXCL12 protein, human
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Chemokine CXCL12
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NF-kappa B
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Nuclear Proteins
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PI3KCA protein, human
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RAC1 protein, human
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RNA, Messenger
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Transcription Factors
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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MMP2 protein, human
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Matrix Metalloproteinase 2
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rac1 GTP-Binding Protein
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Curcumin